Immediate and Long-Term Impact of Early-Life Trauma

描述(由申请人提供)：童年早期的创伤是成人发展为焦虑症的主要危险因素，如创伤后应激障碍(PTSD)。确定这种关系的根本原因仍然具有极大的挑战性。特别是，确定创伤时大脑的功能状态如何导致创伤后应激障碍及其神经基础仍然是一个难以实现的目标。此前，使用动物模型的研究主要集中在母体分离程序作为早期生活压力来源的研究上。我们建议使用痛苦的足部电击作为创伤程序，因为这是虐待儿童的主要组成部分。这一过程在不同的出生后年龄呈现时，对恐惧学习的个体发生产生了重要的见解。我们的实验室在成人恐惧条件作用方面有丰富的经验，在成熟动物中的上述程序导致对依赖于杏仁核(AMY)、海马体(HIPP)和前额叶皮质(PFC)的创伤的终身记忆。重要的是，如果这种恐惧体验足够强烈，它会导致持续存在过度夸大恐惧反应的脆弱性，即使是对最初创伤的轻微提醒。这种敏感化的恐惧反应是创伤后应激障碍的中心特征。我们的方法根据早期生活创伤的发生时间确定了3个关键假设(图A)：1)阶段1的早期产后创伤：在AMY功能成熟之前，恐惧学习系统不能被充分激活。2)第二阶段的产后中期创伤：在AMY功能成熟后，但在海马语境处理通路成熟之前，不能建立关联性恐惧反应，但非关联性恐惧敏感化和神经内分泌反应仍然存在。3)第三阶段的晚期产后创伤：随着两个系统的成熟，两个系统都可以获得适当的条件反应，成人可以持续增强基于杏仁核的恐惧学习。为了验证这些假设，我们建议确定恐惧神经回路对早期生活创伤的功能状态，以及这如何有助于成人创伤后应激障碍相关症状的发展。这将通过使用神经解剖学方法来完成，在该方法中，我们能够表征杏仁核及其相关传入和传出脑区域内的早期基因的表达，以响应出生后早期(P8)、中期(P19)和晚期(P35)的重复足震伤。接下来，我们讨论创伤在这些发育时间点对成人恐惧和神经内分泌功能的长期影响。通过了解成熟的大脑如何容易受到早期生活创伤的影响，这可以为理解PTSD等衰弱焦虑症的潜在机制提供很好的见解。

DESCRIPTION (provided by applicant): Trauma during early childhood is a major risk factor for the adult development of anxiety disorders such as post-traumatic stress disorder (PTSD). Determining the underlying causes of this relationship has remained extraordinarily challenging. In particular, determining how the functional state of the brain at the time of trauma contributes to PTSD and its neural underpinnings remains an elusive goal. Prior efforts, using animal models have mainly focused on maternal-separation procedures as early life stressors. We propose the use of painful foot shocks as a trauma procedure given that it is a major component of child abuse. This procedure when presented at different post-natal ages has yielded important insights into the ontogeny of fear learning. Our laboratory has substantial experience in adult fear conditioning, with the above procedure in the mature animal resulting in a life-long memory of the trauma that depends on the amygdala (AMY), hippocampus (HIPP) and prefrontal cortex (PFC). Importantly, if this fear experience is strong enough it results in a sustained vulnerability to over-exaggerate fear responses even to mild reminders of the original trauma. This sensitized fear response is a central characteristic of PTSD. Our approach identifies 3 key hypotheses based on the timing of early life trauma (figure A): 1) Early Post-natal trauma during Stage 1: Prior to the functional maturation of AMY, fear learning systems cannot be sufficiently activated. 2) Middle Post-natal trauma during Stage 2: After the functional maturation of the AMY, but prior to the maturation of hippocampal context processing pathways, associative fear responses cannot be established, yet non-associative sensitization of fear and neuroendocrine responses persist. 3) Late Post-natal trauma during Stage 3: With the maturation of both systems both appropriate conditional responses can be acquired as well as a sustained adult enhancement of amygdala-based fear learning. To test these hypothesize we propose to identify the functional status of the fear neural circuits to early life trauma and how this contributes to development of adult PTSD related symptomology. This will be accomplished by using a neuroanatomical approach in which we are capable of characterizing the expression of immediately early genes within the amygdala and its associated afferent and efferent brain regions in response to repeated footshock trauma during early (P8), middle (P19) and late (P35) post-natal development. Next we address the long-lasting impact of trauma at these developmental time points on adult fear and neuroendocrine function. By understanding the how the maturing brain is susceptible to early-life trauma, this could provide great insight into mechanisms underlying a debilitating anxiety disorders such as PTSD.